Pharmacological Modulation of Cognitive Test Solution in Mice of Two Genotypes.

Mice of two strains selected for successful solution of "object permanence" test and for lack of such solution demonstrated the differential reaction to injections of two drugs. The effects of injections of atomoxetine. which blocks the noradrenaline reuptake, and of 'non-benzodiazepine" anxiolytic afobazol was different. The success of solutions increased in mice selected for this test "non-solution": and decreased or was inefficient in mice, selected for successful solution of object permanence cognitive test.

Evaluation of SLC6A2 and CYP2D6 polymorphisms' effects on atomoxetine treatment in attention deficit and hyperactivity disorder.

BACKGROUND: There is insufficient replicated data to establish a relationship between the polymorphisms of SLC6A2 and CYP2D6 and the treatment responses of atomoxetine (ATX) in ADHD. We focused on evaluating the effect of top-line single nucleotide polymorphisms (SNPs) in SLC6A2 and CYP2D6 on the ATX treatment response in attention deficit and hyperactivity disorder (ADHD). METHODS: Of 160 patient records, 34 patients who met the inclusion criteria were evaluated to determine the relationship between genotypes of ten SNPs (six of SLC6A2 and four of CYP2D6) and ATX treatment response. Additionally, the connection between SNPs of CYP2D6 and the severity of side effects associated with ATX was analyzed in 37 patients, including the 34 study patients, and three patients discontinued because of ATX-dependent side effects. RESULTS: All six polymorphisms we studied in SLC6A2 were associated with the treatment response of ATX. Clinical improvement in oppositional defiant disorder symptoms of patients with ADHD was only observed in carriers of the homozygous "C" allele of rs3785143 (podd = 0.026). We detected an association between higher CGI-side-effect severity scores and the "TT" genotype of rs1065852 polymorphism in CYP2D6 (p = 0.043). CONCLUSIONS: The findings of this study suggest that genotypes of polymorphisms within the SLC6A2 and CYP2D6 may play an influential role in treatment response or the severity of side effects associated with ATX in ADHD patients.

Attenuated responses to attention-modulating drugs in the neuroligin-3R451C mouse model of autism.

Attention deficits are frequently reported within the clinical autism population. Despite not being a core diagnostic feature, some aetiological theories place atypical attention at the centre of autism development. Drugs used to treat attention dysfunction are therefore increasingly prescribed to autistic patients, though currently off-label with uncertain efficacy. We utilised a rodent-translated touchscreen test of sustained attention in mice carrying an autism-associated R451C mutation in the neuroligin-3 gene (Nlgn3R451C). In doing so, we replicated their cautious but accurate response profile and probed it using two widely prescribed attention-modulating drugs: methylphenidate (MPH) and atomoxetine (ATO). In wild-type mice, acute administration of MPH (3 mg/kg) promoted impulsive responding at the expense of accuracy, while ATO (3 mg/kg) broadly reduced impulsive responding. These drug effects were absent in Nlgn3R451C mice, other than a small reduction in blank touches to the screen following ATO administration. The absence of drug effects in Nlgn3R451C mice likely arises from their altered behavioural baseline and underlying neurobiology, highlighting caveats to the use of classic attention-modulating drugs across disorders and autism subsets. It further suggests that altered dopaminergic and/or norepinephrinergic systems may drive behavioural differences in the Nlgn3R451C mouse model of autism, supporting further targeted investigation.

Refractory cardiogenic shock due to atomoxetine overdose rescued by venoarterial extracorporeal membrane oxygenation: A case report.

Background: Atomoxetine, a selective norepinephrine reuptake inhibitor for attention-deficit hyperactivity disorder, may lead to severe complications, notably cardiac issues, upon overdose. We present a unique case of venoarterial extracorporeal membrane oxygenation (VA-ECMO) rescue for atomoxetine-induced cardiogenic shock. Case Presentation: We report a 30-year-old man who, after ingesting a significant overdose of atomoxetine, experienced seizures and severe cardiogenic shock, necessitating VA-ECMO for resuscitation. While prior reports have noted cardiovascular complications like QTc prolongation and Takotsubo cardiomyopathy following atomoxetine overdose, this case is notable for its life-threatening circulatory failure, which required ECMO intervention. Swift recognition coupled with VA-ECMO initiation, endoscopic medication removal, intravenous lipid emulsion, and activated charcoal may have played a pivotal role in stabilizing the patient and facilitating recovery. Conclusion: Healthcare practitioners should recognize the severe cardiac complications of atomoxetine overdose. Careful monitoring with ECG and echocardiography, along with providing intensive care, is crucial in managing critical cases.

Implication of locus coeruleus dysfunction in Prader-Willi syndrome: Insights from a mouse model.

Prader-Willi syndrome (PWS) is a multisystemic disorder. Notably, many characteristic symptoms of PWS are correlated with locus coeruleus norepinephrine system (LC-NE) dysfunction, including impairment in arousal, learning, pain modulation, and stress-induced negative affective states. Although electrophysiological experiments in necdin-deficient mice, an established PWS animal model, have revealed decreased spontaneous neuronal firing activity in the LC and impaired excitability, the behavioral phenotypes related to LC-NE dysfunction remain unexplored. In this study, heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygous (+m/-p) animals. Compared to WT mice, Ndn + m/-p mice demonstrated impaired visual-spatial memory in the Y-maze test, reduced social interaction, impaired sexual recognition, and shorter falling latency on the Rotarod. Using the open field test (OFT) and elevated plus maze (EPM), we observed similar locomotion activity of Ndn + m/-p and WT mice, but Ndn + m/-p mice were less anxious. After acute restraint, Ndn + m/-p mice exhibited significant impairment in stress-induced anxiety. Additionally, the plasma norepinephrine surge following exposure to acute restraint stress was also impaired. Pretreatment with atomoxetine, a norepinephrine reuptake inhibitor aimed to enhance LC function, restored Ndn + m/-p mice to exhibit a normal response to acute restraint stress. Furthermore, by employing chemogenetic approaches to facilitate LC neuronal firing, post-stress anxious responses were also partially rescued in Ndn + m/-p mice. These data strongly suggest that LC dysfunction is implicated in the pathogenesis of stress-related neuropsychiatric symptoms in PWS. Manipulation of LC activity may hold therapeutic potential for patients with PWS.

Quantification of ADHD medication in biological fluids of pregnant and breastfeeding women with liquid chromatography: a comprehensive review.

Attention Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that has long been considered a concern only in the pediatric population. However, symptoms often sustain into adulthood and may require medication. For women with ADHD, this also means dealing with the disorder during the reproductive period. Medication safety during pregnancy and breastfeeding is a critical concern, and the potential transfer of ADHD medication to infants remains a topic of scientific interest. The quantification of ADHD medications in both maternal blood and breast milk are vital for understanding their pharmacokinetics and potential exposure risks for (nursing) infants. This review aims (1) to compile and critically assess existing research on the transfer of ADHD medications into breast milk and the potential implications for nursing infants and (2) to provide a comprehensive overview and discussion of the literature regarding the quantification of methylphenidate, amphetamine, atomoxetine, viloxazine, guanfacine, clonidine and bupropion in the blood, urine, oral fluid, and breast milk with liquid chromatography. A literature search was conducted using PubMed, Scopus, and Web of Science, to identify relevant articles published from January 2014 up to December 2023. We illustrate the lack of methods to simultaneously monitor multiple ADHD medications as well as the lack of developed methods for breast milk. Finally, we highlight the need for continued research to refine our understanding of medication transfer into breast milk and potential risks, and to develop clinical guidelines to support mothers with ADHD in making informed choices regarding medication use during pregnancy and lactation.

Atomoxetine for Intradialytic Hypotension in a Patient on Hemodialysis: A Case Report.

Intradialytic hypotension significantly affects patient safety and clinical outcomes during hemodialysis. Despite various pharmacological and nonpharmacological interventions, effective management remains elusive. In this report, we detail a case of intradialytic hypotension in a male patient in his 40s, undergoing hemodialysis with a history of polycystic kidney disease. Eight years ago, the patient underwent bilateral nephrectomy because of a severe cystic infection, after which his systolic blood pressure (BP) persistently remained at 50-70 mm Hg during dialysis sessions. The initial treatment strategy for hypotension included fludrocortisone, midodrine, and prednisolone, leading to a slight temporary increase in BP, which subsequently declined. As the patient's condition deteriorated, the administration of norepinephrine or dopamine became necessary to sustain BP during dialysis. Given the patient's resistance to these treatments, a daily dose of 25 mg of atomoxetine was introduced. Following this treatment, there was a gradual improvement in the patient's vertigo, weakness, and BP. This case illustrates that low-dose atomoxetine can alleviate symptoms and elevate BP in patients experiencing severe intradialytic hypotension during hemodialysis.

Long-life triclosan exposure induces ADHD-like behavior in rats via prefrontal cortex dopaminergic deficiency.

In recent years, exposure to triclosan (TCS) has been linked to an increase in psychiatric disorders. Nonetheless, the precise mechanisms of this occurrence remain elusive. Therefore, this study developed a long-life TCS-exposed rat model, an SH-SY5Y cell model, and an atomoxetine hydrochloride (ATX) treatment model to explore and validate the neurobehavioral mechanisms of TCS from multiple perspectives. In the long-life TCS-exposed model, pregnant rats received either 0 mg/kg (control) or 50 mg/kg TCS by oral gavage throughout pregnancy, lactation, and weaning of their offspring (up to 8 weeks old). In the ATX treatment model, weanling rats received daily injections of either 0 mg/kg (control) or 3 mg/kg ATX via intraperitoneal injection until they reached 8 weeks old. Unlike the TCS model, ATX exposure only occurred after the pups were weaned. The results indicated that long-life TCS exposure led to attention-deficit hyperactivity disorder (ADHD)-like behaviors in male offspring rats accompanied by dopamine-related mRNA and protein expression imbalances in the prefrontal cortex (PFC). Moreover, in vitro experiments also confirmed these findings. Mechanistically, TCS reduced dopamine (DA) synthesis, release, and transmission, and increased reuptake in PFC, thereby reducing synaptic gap DA levels and causing dopaminergic deficits. Additional experiments revealed that increased DA concentration in PFC by ATX effectively alleviated TCS-induced ADHD-like behavior in male offspring rats. These findings suggest that long-life TCS exposure causes ADHD-like behavior in male offspring rats through dopaminergic deficits. Furthermore, ATX treatment not only reduce symptoms in the rats, but also reveals valuable insights into the neurotoxic mechanisms induced by TCS.

Development and In vivo Evaluation of Atomoxetine Hydrochloride ODMTs in a Nicotine-induced Attention Deficit Hyperactivity Disorder (ADHD) Model in Rats.

The current study aimed to evaluate the efficacy of orally administered rapid mini-tablets containing atomoxetine hydrochloride (ODMT) relative to the conventional capsule formulation of atomoxetine hydrochloride (ATO). To mask the bitter taste of ATO and render it more palatable for pediatric administration in individuals with Attention Deficit Hyperactivity Disorder (ADHD), an inclusion complex of ATO with ß-cyclodextrin (ß-CD) was synthesized. The ODMT and conventional capsule ATO formulations were administered orally to a cohort of ADHD rat pups born to nicotine-exposed dams, facilitating an in vivo efficacy assessment. Behavioral assays, including the open field test, novel object recognition test, and Barnes maze test, were conducted pre- and post-administration of the therapeutics. The outcomes suggested that the ODMT formulation, incorporating ATO-ß-CD inclusion complexes, shows promise as a viable alternative to the capsule form of ATO. Conclusively, the preparation of the ATO-ß-CD complexes and ODMTs leveraged a factorial experimental design, with the animal model being subjected to nicotine-induced hyperactivity to provide a unique evaluative framework for the ODMT formulation under development.

Development of a fluorescent nano-sensing probe for atomoxetine analysis: Additional clinical pharmacokinetic study.

Atomoxetine is a psychostimulant drug used for the treatment of attention-deficit/hyperactivity disorder (ADHD) symptoms in people with autism. Herein, eco-friendly fluorescent carbon quantum dots (CQDs) were synthesized using black-eyed pea beans and characterized for the purpose of quantifying atomoxetine in pharmaceutical capsules and human plasma. The selectivity of these CQDs towards atomoxetine was improved by functionalizing their surface with an atomoxetine-tetraphenylborate ion complex. The quantification of atomoxetine is based on measuring the fluorescence quenching of the functionalized CQDs in response to varying concentrations of atomoxetine. The Stern-Volmer plot was employed to investigate the mechanism through which atomoxetine quenches the fluorescence intensity of the CQDs. The outcomes indicated a dynamic quenching mechanism. The applied method was optimized and validated in compliance with ICH requirements, resulting in excellent linearity across the concentration range of 50-800 ng/mL. The developed method was successfully used to quantify atomoxetine in pharmaceutical dosage form and human plasma with acceptable accuracy and precision outcomes. In addition, the method was applied for clinical pharmacokinetic study of atomoxetine in the plasma of children diagnosed with both autism and ADHD. Atomoxetine was rapidly absorbed after a single oral dose of 10 mg, reaching maximum concentration within two hours and having a half-life (t1/2) of 3.11 h. Moreover, the method demonstrates a notable degree of eco-friendliness, as evidenced by two greenness evaluation metrics; Green Analytical Procedure Index (GAPI) and Analytical GREEnness (AGREE).

Growing evidence of pharmacotherapy effectiveness in managing attention-deficit/hyperactivity disorder in young children with or without autism spectrum disorder: a minireview.

Many children with autism spectrum disorder (ASD) also have attention-deficit/hyperactivity disorder (ADHD). ADHD in children is associated with increased risk of negative outcomes, and early intervention is critical. Current guidelines recommend psychosocial interventions such as behavioral training as the first line of therapy in managing ADHD symptoms in children with or without ASD. Where symptoms are refractory to these interventions, medications such as stimulants, α2-adrenergic agonist inhibitors, selective norepinephrine reuptake inhibitors, and second-generation antipsychotics are recommended. However, these pharmacotherapies do not have regulatory approval for use in children of preschool age, and evidence on their safety and efficacy in this population has historically been very limited. Since publication of the current guidelines in 2020, several new randomized controlled trials and real-world studies have been published that have investigated the efficacy and tolerability of these medications in preschool children with ADHD, with or without comorbid ASD. Here, we provide a review of the key findings of these studies, which suggest that there is growing evidence to support the use of pharmacological interventions in the management of ADHD in preschool children with comorbid ASD.

Atomoxetine: toxicological aspects of a new treatment for Attention Deficit Hyperactivity Disorder in Brazil.

Atomoxetine is a drug widely used for the treatment of the attention deficit hyperactivity disorder (ADHD) with reduced risk of adverse motor reactions and chemical dependence. However, the pharmacokinetics characteristics as well as the toxicological risk of atomoxetine deserves further investigation to comprehensively analyze the therapeutic and safety aspects of this drug. This study aimed to predict the physicochemical profile and medicinal chemistry characteristics of atomoxetine, alongside its pharmacokinetic properties-namely absorption, distribution, metabolism, and excretion-as well as its toxicology (ADMET) potential through the utilization of web-based in silico tools. This research emphasizes predicted physicochemical, medicinal chemistry, and absorption parameters of atomoxetine that could influence the efficacy and safety of this drug for ADHD treatment. Additionally, atomoxetine also presents noteworthy predicted risks of hepatotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity, respiratory system toxicity, skin toxicity, and carcinogenicity. These findings underscore the necessity for further assessments of atomoxetine's safety profile, particularly considering different patient populations and durations of drug treatment. The data reported here from in silico predictions suggest that closer monitoring is warranted when atomoxetine is administered to patients with ADHD. Moreover, controlled studies detailing reliable protocols for personalized dosing, considering the multifactorial variability in metabolism efficiency and toxicological potential, would enable a more comprehensive assessment of atomoxetine's safety profile.

Current nonstimulant medications for adults with attention-deficit/hyperactivity disorder.

INTRODUCTION: Stimulants, including methylphenidate and amphetamines, are the first-line pharmacological treatment of ADHD in adults. However, in patients who do not respond or poorly tolerate stimulants, non-stimulant medications are usually recommended. AREAS COVERED: The authors provide a narrative review of the literature on non-stimulant treatments for adult ADHD, including controlled and observational clinical studies conducted on adult samples. Atomoxetine has been extensively studied and showed significant efficacy in treating adult ADHD. Issues related to dosing, treatment duration, safety, and use in the case of psychiatric comorbidity are summarized. Among other compounds indicated for ADHD in adults, antidepressants sharing at least a noradrenergic or dopaminergic component, including tricyclic compounds, bupropion, and viloxazine, have shown demonstratable efficacy. Evidence is also available for antihypertensives, particularly guanfacine, as well as memantine, metadoxine, and mood stabilizers, while negative findings have emerged for galantamine, antipsychotics, and cannabinoids. EXPERT OPINION: While according to clinical guidelines, atomoxetine may serve as the only second-line option in adults with ADHD, several other nonstimulant compounds may be effectively used in order to personalize treatment based on comorbid conditions and ADHD features. Nevertheless, further research is needed to identify and test more personalized treatment strategies for adults with ADHD.

The effects of chronic administration of stimulant and non-stimulant medications on executive functions in ADHD: A systematic review and meta-analysis.

Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with executive function deficits that are improved with medications. However, meta-analyses of stimulant effects on cognition have mostly tested single-dose effects, and there is no meta-analysis of non-stimulant effects. This systematic review and meta-analysis tested the clinically more relevant longer-term effects of Methylphenidate (20 studies; minimum 1 week) and Atomoxetine (8 studies; minimum 3 weeks) on reaction time, attention, inhibition, and working memory, searching papers on PubMed, Embase, Ovid MEDLINE, and PsycINFO. The meta-analysis of 18 studies in 1667 subjects showed that methylphenidate was superior to placebo in all cognitive domains with small to medium effect sizes (Hedges g of 0.34-0.59). The meta-analysis of atomoxetine included 7 studies in 829 subjects and showed no effects in working memory, but superior effects in the other domains with medium to large effect sizes (Hedge's g of 0.36-0.64). Meta-regression analysis showed no drug differences on cognitive effects. The meta-analyses show for the first time that chronic Methylphenidate and Atomoxetine have comparable effects of improving executive functions in people with ADHD.

Norepinephrine Reuptake Inhibition, an Emergent Treatment for Neurogenic Orthostatic Hypotension.

The NET (norepinephrine transporter) is situated in the prejunctional plasma membrane of noradrenergic neurons. It is responsible for >90% of the norepinephrine uptake that is released in the autonomic neuroeffector junction. Inhibitors of this cell membrane transporter, known as norepinephrine reuptake inhibitors (NRIs), are commercially available for the treatment of depression and attention deficit hyperactivity disorder. These agents increase norepinephrine levels, potentiating its action in preganglionic and postganglionic adrenergic neurons, the latter through activation of α-1 adrenoreceptors. Previous studies found that patients with neurogenic orthostatic hypotension can improve standing blood pressure and reduce symptoms of neurogenic orthostatic hypotension after a single administration of the selective NRI atomoxetine. This effect was primarily observed in patients with impaired central autonomic pathways with otherwise normal postganglionic sympathetic fibers, known as multiple system atrophy. Likewise, patients with normal or high norepinephrine levels may benefit from NRIs. The long-term efficacy of NRIs for the treatment of neurogenic orthostatic hypotension-related symptoms is currently under investigation. In summary, an in-depth understanding of the pathophysiology of neurogenic orthostatic hypotension resulted in the discovery of a new therapeutic pathway targeted by NRI.

Recent advances in pharmacological management of attention-deficit/hyperactivity disorder: moving beyond stimulants.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder characterized by impairing inattention and/or hyperactivity and impulsivity in children and adults. Although medications have been available to treat ADHD symptoms for decades, many are stimulant formulations. Stimulants, such as amphetamine and methylphenidate, are available in more than two dozen formulations, but all have similar adverse effects and carry a risk of misuse and dependence. AREAS COVERED: In the United States (US), several nonstimulants are available to treat ADHD. Two, including atomoxetine and viloxazine extended-release (ER), are approved by the Food and Drug Administration for the treatment of ADHD in children and adults. Two others, clonidine ER and guanfacine ER, are only approved for children and adolescents in the US. Several other compounds are under investigation. Drugs in Phase 3 trials include centanafadine, solriamfetol, and L-threonic acid magnesium salt. Efficacy and safety data for nonstimulants is presented. EXPERT OPINION: Although many effective formulations for the treatment of ADHD are available, more than 33% of children and 50% of adults discontinue treatment during the first year. The lack of individual drug response and tolerability are reasons many stop treatment. The development of new nonstimulants may offer hope for patients who need medication alternatives.

Attention-deficit/hyperactivity disorder in pregnancy and the postpartum period.

Attention-deficit/hyperactivity disorder is a childhood-onset neurodevelopmental disorder that frequently persists into adulthood with 3% of adult women having a diagnosis of attention-deficit/hyperactivity disorder. Many women are diagnosed and treated during their reproductive years, which leads to management implications during pregnancy and the postpartum period. We know from clinical practice that attention-deficit/hyperactivity disorder symptoms frequently become challenging to manage during the perinatal period and require additional support and attention. There is often uncertainty among healthcare providers about the management of attention-deficit/hyperactivity disorder in the perinatal period, particularly the safety of pharmacotherapy for the developing fetus. This guideline is focused on best practices in managing attention-deficit/hyperactivity disorder in the perinatal period. We recommend (1) mitigating the risks associated with attention-deficit/hyperactivity disorder that worsen during the perinatal period via individualized treatment planning; (2) providing psychoeducation, self-management strategies or coaching, and psychotherapies; and, for those with moderate or severe attention-deficit/hyperactivity disorder, (3) considering pharmacotherapy for attention-deficit/hyperactivity disorder, which largely has reassuring safety data. Specifically, providers should work collaboratively with patients and their support networks to balance the risks of perinatal attention-deficit/hyperactivity disorder medication with the risks of inadequately treated attention-deficit/hyperactivity disorder during pregnancy. The risks and impacts of attention-deficit/hyperactivity disorder in pregnancy can be successfully managed through preconception counselling and appropriate perinatal planning, management, and support.

[Attention deficit hyperactivity disorder in adults]. / Sindrom defitsita vnimaniya s giperaktivnost'yu u vzroslykh.

The article presents a review of scientific publications devoted to the study of the characteristics of the clinical picture and the dynamics of the main symptoms in adult patients with attention deficit hyperactivity disorder (ADHD). The authors present current data on the prevalence of this disease, leading clinical manifestations and the most common comorbid pathology. Research data on the impact of ADHD in adulthood on educational and professional activities are presented, and the economic and criminological aspects of ADHD are considered. The main methods of psychotherapeutic correction and pharmacological therapy are presented.